Oral Abstract Session 01 - Global HIV Vaccine Enterprise
Oral Abstract Session 01 - Global HIV Vaccine Enterprise
Oral Abstract Session 01 - Global HIV Vaccine Enterprise
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POSTERS<br />
Posters<br />
Topic 3: B Cell Immunology and Antibody Functions<br />
P03.39<br />
Antibody Subclass Skewing Predicts Enhanced ADCC<br />
Activity in Both Natural Infection and Vaccination<br />
A. Dugast 1 , A. Chung 1 , Y. Chang 1 , A. Licht 1 , M. Ackerman 2 ,<br />
G. Alter 1<br />
1 Ragon Institute, Charlestown, MA, France; 2 Thayer School of<br />
Engineering, Dartmouth College, Hanover, NH, USA<br />
Background: The innate immune recruiting property of<br />
antibodies are elicited following an Fc/Fc-receptor interaction.<br />
We previously demonstrated that <strong>HIV</strong>-specific antibodies<br />
from elite controllers (ECs) robustly recruit NK cells to mediate<br />
antibody dependent cellular viral inhibition (ADCVI) compared<br />
to antibodies from chronic progressors. To gain further insights<br />
into the biophysical properties of EC antibodies that enable<br />
them to recruit Fc-effector functions so robustly, we performed<br />
at 24 dimensional analysis (including specificity, isotype, Fcreceptor<br />
affinity, and function) of the antibody profiles mounted<br />
in ECs and <strong>HIV</strong>-progressors to define the humoral signature(s)<br />
associated with most robust innate immune recruiting activity<br />
Methods: A total of thirty donors were included in this study<br />
(10 untreated chronics, 10 treated chronics, 10 ECs). Anti-gp120,<br />
p24, gp41 and gp140 antibody binding titers were quantified<br />
by ELISA and a customized-multiplex <strong>HIV</strong> binding assay against<br />
<strong>HIV</strong> recombinant gp120, p24, gp41 and gp140. Fc-receptor<br />
affinity was analyzed by Biacore. ADCVI, ADCC, and ADCP were<br />
quantified as previously described<br />
Results: While no differences were observed in the antibody<br />
binding titer between ECs and chronic progressors against<br />
gp120 or gp41, we showed that ECs exhibited a higher level of<br />
p24-specific antibodies, associated with robust ADCVI activity.<br />
Moreover, humoral responses in ECs were skewed toward IgG1<br />
and IgG3 responses, compared to chronic progressors, that<br />
strongly predicted enhanced ADCVI activity. Similar skewing of<br />
antibody responses were observed in RV144 vaccinees, strongly<br />
suggesting that specific cues elicited within this vaccine trial may<br />
have resulting in the induction of highly potent innate immune<br />
recruiting antibodies similar to those found in ECs<br />
Conclusion: Overall, ECs elicit a skewed humoral immune<br />
response marked by the preferential selection of <strong>HIV</strong> specific<br />
IgG1 and IgG3 antibody subclasses, that parallels the humoral<br />
immune responses observed in RV144 vaccinees. Therefore,<br />
characterizing these unique antiviral capacities may provide<br />
critical information on humoral responses that could potentiate<br />
vaccine-induced responses<br />
136<br />
AIDS <strong>Vaccine</strong> 2<strong>01</strong>2<br />
P03.40<br />
A Novel Rabbit Monoclonal Antibody Platform to<br />
Dissect the Diverse Repertoire of Antibody Epitopes<br />
for <strong>HIV</strong>-1 Env Immunogen Design<br />
Y. Chen 1 , M. Vaine 1 , X. Kong 2 , D. Montefiori 3 , S. Wang 1 , S. Lu 1<br />
1 University of Massachusetts Medical School, Worcester, MA,<br />
USA; 2 New York University School of Medicine, New York, NY,<br />
USA; 3 Duke University Medical Center, Durham, NC, USA<br />
Background: The majority of available monoclonal antibodies<br />
(mAbs) in the current <strong>HIV</strong> vaccine field are generated from<br />
<strong>HIV</strong>-1 infected people. In contrast, preclinical immunogenicity<br />
studies have mainly focused on polyclonal antibody responses in<br />
experimental animals. Although rabbits have been widely used<br />
for antibody studies, there has been no report of using rabbit<br />
mAbs to dissect the specificity of antibody responses for AIDS<br />
vaccine development.<br />
Methods: Here we report the production of a panel of 12 mAbs<br />
from one NZW rabbit that was immunized with a <strong>HIV</strong>-1 JR-FL<br />
gp120 DNA prime and protein boost vaccination regimen.<br />
Results: These rabbit mAbs recognized a diverse repertoire of<br />
epitopes. Besides the traditional highly immunogenic V3 region,<br />
these mAbs recognized several previously underappreciated<br />
epitopes in the C1, C4, and C5 regions. Nine mAbs showed<br />
cross-reactivity against gp120s of clades other than clade B. At<br />
least three mAbs showed neutralizing activities with various<br />
breadth and potency. Increased somatic mutation percentage<br />
and long CDR3 were observed with some of the rabbit mAbs.<br />
More interestingly, phylogenic tree analysis showed that the<br />
heavy chain of mAbs recognizing the same region on gp120<br />
were segregated into an independent subtree, implicating that<br />
these mAbs may derive from the same B cell precursor. Crystal<br />
structures of several rabbit mAbs suggested that these rabbit<br />
mAbs generated from vaccines mimic the binding modes of wellcharacterized<br />
human mAbs isolated from infected individuals.<br />
Conclusion: Therefore, isolation of mAbs from vaccinated<br />
rabbits provides us an opportunity to study the evolution<br />
and affinity maturation of <strong>HIV</strong>-1 Env-specific mAbs elicited by<br />
candidate AIDS vaccines.
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